1. Field of the Invention
The present invention provides novel asymmetric urea compounds, particularly asymmetric urea compounds capable of binding with high selectivity and/or high affinity to N-Acylated alpha-linked L-amino dipeptidaase (NAALADase) (also known as glutamate carboxypeptidase II; GCP II) and/or prostate specific membrane antigen (PSMA). This invention also provides pharmaceutical compositions comprising such urea compounds. Additionally this invention provides imaging methods for localizing NAALADase and/or PSMA in tissues or cells using radiolabeled asymmetric urea compounds of the invention. The invention further provides treatment methods comprising administration of a high energy radiolabeled asymmetric urea to a patient, particularly patients suffering from prostate cancer.
2. Background
In the brain, the metalloprotease, glutamate carboxypeptidase II (GCP II; EC 3.4.17.21) cleaves N-acetyl-aspartyl-glutamate (NAAG) to N-acetyl-aspartate (NAA) and glutamate. The roles of GCP II in the brain are to terminate the neurotransmitter activity of NAAG and to produce glutamate that is then free to act as its various receptor subtypes.
GCP II and PSMA are very similar enzymes, such that an imaging probe for GCP II may serve useful to image PSMA. PSMA is expressed in a variety of normal and malignant tissues in and outside of the central nervous system (CNS). Immunohistochemistry using the anti-PSMA antibody 7E11-C5 has shown PSMA to have a fairly restricted pattern of expression in human tissues, with the highest levels of activity demonstrated in a subset of proximal renal tubules, prostate epithelium, and within the duodenum and colon. An immuno-cytochemical study that focused on the brain distribution of GCP II revealed staining of areas previously noted to contain immunoreactivity for NAAG, the natural substrate for GCP II. Those areas included the basal ganglia, hippocampus, substantia nigra, among others, and included regions that did not demonstrate NAAG immunoreactivity. A study that employed 3H-NAAG demonstrated a 14-fold elevation of PSMA in human prostate cancer relative to normal prostate tissue. PSMA expression is highest in high-grade and hormone-refractory disease. Using a panel of anti-PSMA antibodies, PSMA immunoreactivity has been demonstrated in tumor-associated neovasculature in a host of tumors, including breast, colon, and lung.
GCP II also possesses 87% sequence homology with the prostate-specific membrane antigen (PSMA). GCP II and PSMA exhibit some differences in substrate specificity and cellular localization. More particularly, GCP II has only a membrane bound form, whereas PSMA is found both in cell membranes and within cytosol. Notwithstanding the differences in substrate specificity and cellular localization, the enzymes have been shown to have similar pharmacological profiles.
Kozikowski et al recite a series of inhibitors of GCP II that maintain a structural motif similar to that of the phosphonic bis-dicarboxylic acid, 2-[(2,4-Dicarboxy-butyl)-hydroxy-phosphinoylmethyl]-pentanedioic acid, which is a potent inhibitor of GCP II, but has the central CH2P(O)(OH)CH2 group replaced with a urea group (J. Med. Chem. 2001 44: 298-301).
2-[(2,4-Dicarboxy-butyl)-hydroxy-phosphinoylmethyl]-pentanedioic acid
U.S. Pat. No 6,479,470 issued to Kozikowski reports a series of compounds according to the formula:

Where X is selected from —COOH, —C(O)NHOH, —C(O)NH2, —C(S)SH, —SO3H, —SO2H, —SOH, —SeO3H, —SeOH, —S(O)2NH2, —P(O)(OH)2, and —P(OH)2.
J. Frangioni teaches, in WO 02/098885 and WO 02/38190, a series of phosphonate, bisphosphonate and ester compounds and the use of same as imaging agents. Frangioni, in WO 01/72958, also teaches the use of various peptides in the diagnosis and treatment of diseases including bladder cancer.
mAb imaging and therapy for prostate cancer based on agents that bind either to intra- or extra-cellular domains of PSMA has been reported and includes Prostascint, a clinical agent that utilizes single photon emission computed tomography (SPECT) (Cancer Res. 1990, 50:6423-6429; Cancer Metastasis Rev. 1999, 18:483-490; and Cancer Res. 2000, 60:6095-6100).
It would be desirable to have a family of compounds, including radiolabeled compounds, having high affinity for GCP and/or PSMA, which can be readily prepared.